tbuckley/cabot-search huggingface dataset:
Chromatin remodeling (SWI/SNF) complexes, cancer, and response to immunotherapy
Authors: Nithya Krishnamurthy, Shumei Kato, Scott Lippman, Razelle Kurzrock
Journal: Journal for ImmunoTherapy of Cancer (2022)

Chromatin regulation involves four subfamilies composed of ATP-dependent multifunctional protein complexes that remodel the way DNA is packaged. The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex subfamily mediates nucleosome reorganization and hence activation/repression of critical genes. The SWI/SNF complex is composed of the BRG-/BRM-associated factor and Polybromo-associated BAF complexes, which in turn have multiple subunits. Significantly, ~20% of malignancies harbor alterations in &gt;1 of these subunits, making the genes encoding SWI/SNF family members among the most vulnerable to genomic aberrations in cancer. ARID1A is the largest subunit of the SWI/SNF complex and is altered in ~40%–50% of ovarian clear cell cancers and ~15%–30% of cholangiocarcinomas, in addition to a variety of other malignancies. Importantly, outcome was improved after immune checkpoint blockade (ICB) in patients with ARID1A -altered versuss wild-type tumors, and this result was independent of microsatellite instability or tumor mutational burden. Another subunit—PBRM1—is mutated in ~40% of clear cell renal cell carcinomas and ~12% of cholangiocarcinomas; there are contradictory reports regarding ICB responsiveness. Two other SWI/SNF subunits of interest are SMARCA4 and SMARCB1. SMARCA4 loss is the hallmark of small cell carcinoma of the ovary hypercalcemic type (and is found in a variety of other malignancies); SMARCA4 germline alterations lead to rhabdoid tumor predisposition syndrome-2; SMARCB1 germline alterations, rhabdoid tumor predisposition syndrome-1. Remarkable, although anecdotal, responses to ICB have been reported in both SMARCA4 -aberrant and SMARCB1 -aberrant advanced cancers. This review focuses on the role that SWI/SNF chromatin remodeling subunits play in carcinogenesis, the immune microenvironment, and in immunotherapy responsiveness.
Membrane anchored IL-18 linked to constitutively active TLR4 and CD40 improves human T cell antitumor capacities for adoptive cell therapy
Authors: Dayana Blokon-Kogan, Maya Levi-Mann, Lior Malka-Levy, Orit Itzhaki, Michal J Besser, Yuval Shiftan, Árpád Szöőr, György Vereb, Gideon Gross, Hinrich Abken, Hadas Weinstein-Marom
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Adoptive transfer of tumor-infiltrating lymphocytes (TILs) or blood T cells genetically redirected by an antitumor TCR or CAR induces a strong antitumor response in a proportion of patients with cancer; however, the therapeutic efficacy is often limited by rapid decline in T cell functions. Coadministering supportive cytokines frequently provokes systemic side effects preventing their broad clinical application. We recently showed that cytokines can be anchored to the cell membrane in a functional fashion and that cytokine receptor signaling can synergize with TLR4 and CD40 signaling. Here, we aimed at augmenting T cell activation by simultaneous signaling through the cytokine receptor, toll-like receptor and TNF-type receptor using IL-18, TLR4 and CD40 as prototypes. Methods Genes were expressed on electroporation of in vitro-transcribed mRNA in CD4 + and CD8 + T cells from healthy donors redirected against melanoma cells with an anti-melanotransferrin CAR and in TILs derived from melanoma patients. Functional assays included the activation of signaling pathways, expression of activation and differentiation markers, cytokine secretion and killing of melanoma target cells. Results To provide IL-18 costimulation to T cells in-cis while avoiding systemic effects, we genetically anchored IL-18 to the T cell membrane, either alone (memIL-18) or fused with constitutively active (ca)TLR4 and caCD40 signaling domains arranged in tandem, creating a synthetic ‘all-in-one’ memIL-18-TLR4-CD40 receptor. MemIL-18-TLR4-CD40, but not memIL-18, triggered strong NF-κB activation in cells lacking the IL-18 receptor, attesting to functionality of the TLR-CD40 moiety. While the membrane-anchored cytokine was found to act mainly in-cis, some T cell activation in-trans was also observed. The electroporated T cells exhibited spontaneous T-bet upregulation and IFN-γ and TNF-α secretion. Melanoma-induced activation of CAR-T cells and TILs as manifested by cytokine secretion and cytolytic activity was substantially augmented by both constructs, with memIL-18-TLR4-CD40 exerting stronger effects than memIL-18 alone. Conclusions Linking membrane anchored IL-18 with caTLR4 and caCD40 signaling in one hybrid transmembrane protein provides simultaneous activation of three T cell costimulatory pathways through one genetically engineered membrane molecule, strongly amplifying T cell functions for adoptive T cell therapy of cancer.
Effect of CD4+ T cell count on treatment-emergent adverse events among patients with and without HIV receiving immunotherapy for advanced cancer
Authors: Thomas A Odeny, Kathryn Lurain, Julius Strauss, Steven P Fling, Elad Sharon, Anna Wright, Javier Martinez-Picado, Teresa Moran, James L Gulley, Maria Gonzalez-Cao, Thomas S Uldrick, Robert Yarchoan, Ramya Ramaswami
Journal: Journal for ImmunoTherapy of Cancer (2022)

The Food and Drug Administration recommends that people living with HIV (PWH) with a CD4+ T cell count (CD4) ≥350 cells/µL may be eligible for any cancer clinical trial, but there is reluctance to enter patients with lower CD4 counts into cancer studies, including immune checkpoint inhibitor (ICI) studies. Patients with relapsed or refractory cancers may have low CD4 due to prior cancer therapies, irrespective of HIV status. It is unclear how baseline CD4 prior to ICI impacts the proportion of treatment-emergent adverse events (TEAE) and whether it differs by HIV status in ICI treated patients.
Statins and immune checkpoint inhibitors: a strategy to improve the efficacy of immunotherapy for cancer?
Authors: Winnie G Vos, Esther Lutgens, Tom T P Seijkens
Journal: Journal for ImmunoTherapy of Cancer (2022)

In the past decade, immune checkpoint inhibitor (ICI) therapy significantly improved the prognosis of patients with cancer. Despite impressive and often unprecedented response rates, a significant portion of the patients fails to benefit from this treatment. Additional strategies to improve ICI efficacy are therefore needed. The widespread clinical use of ICIs has increased our knowledge on the effects of the concomitant use of commonly prescribed drugs on the outcome of ICI treatment. A particular interesting class of drugs in this context are statins. These HMG-CoA reductase inhibitors, which are used to treat hypercholesterolemia and reduce the risk for atherosclerotic cardiovascular disease, are frequently used by patients with (advanced) cancer. This paper addresses the hypothesis that statins improve the efficacy of ICI therapy.
“Management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline.” James D. Chalmers, Megan L. Crichton, Pieter C. Goeminne, <i>et al</i>. <i>Eur Respir J</i> 2021; 57: 2100048.
Journal: European Respiratory Journal (2022)

The ERS living guideline document regarding the management of hospitalised adults with COVID-19 has been updated and republished.The original guideline addressed 11 PICO questions related to the management of hospitalised adults with COVID-19.For the latest version of the guideline, no update was made to five questions, relating to corticosteroids, hydroxychloroquine, lopinavir-ritonavir, remdesivir and interferon-β.New evidence was considered for the remaining six questions, related to anticoagulation, continuous positive airway pressure therapy/high flow nasal oxygen, IL-6 receptor antagonist monoclonal antibodies, azithromycin, azithromycin and hydroxychloroquine combination treatment, and colchicine.Four new PICO questions were added to the guideline update, considering the evidence for treatment with convalescent plasma, specific anti-SARS-CoV-2 monoclonal antibodies, IL-1 receptor antagonist monoclonal antibodies, and JAK inhibitors.A summary of the recommendations can be found in table 1.
Gut commensal E. coli outer membrane proteins activate the host food digestive system through neural-immune communication
Authors: Shengya Geng, Qian Li, Xue Zhou, Junkang Zheng, Huimin Liu, Jie Zeng, Ruizhi Yang, Herui Fu, Fanrui Hao, Qianxu Feng, Bin Qi
Journal: Cell Host & Microbe (2022)
Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia
Authors: Yiman Liu, Qinglan Li, Fatemeh Alikarami, Declan R. Barrett, Leila Mahdavi, Hangpeng Li, Sylvia Tang, Tanweer A. Khan, Mayako Michino, Connor Hill, Lele Song, Lu Yang, Yuanyuan Li, Sheela Pangeni Pokharel, Andrew W. Stamford, Nigel Liverton, Louis M. Renzetti, Simon Taylor, Gillian F. Watt, Tammy Ladduwahetty, Stacia Kargman, Peter T. Meinke, Michael A. Foley, Junwei Shi, Haitao Li, Martin Carroll, Chun-Wei Chen, Alessandro Gardini, Ivan Maillard, David J. Huggins, Kathrin M. Bernt, Liling Wan
Journal: Cancer Discovery (2022)

The chromatin reader eleven-nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line- and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support the clinical translation of this approach. AML is a poor-prognosis disease for which new therapeutic approaches are desperately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent efficacy in MLL-rearranged and NPM1-mutated AML, and determined its mechanisms of action. These biological and chemical insights will facilitate both basic research and clinical translation. This article is highlighted in the In This Issue feature, p. 2483.
<scp>R399E</scp>, A Mutated Form of Growth and Differentiation Factor 5, for Disease Modification of Osteoarthritis
Authors: Anne Gigout, Daniela Werkmann, Stephanie Menges, Christian Brenneis, Frances Henson, Kyra J. Cowan, Djordje Musil, Christian S. Thudium, Hans Gühring, Martin Michaelis, Kerstin Kleinschmidt‐Doerr
Journal: Arthritis & Rheumatology (2022)

To preclinically characterize a mutant form of growth and differentiation factor 5, R399E, with reduced osteogenic properties as a potential disease-modifying osteoarthritis (OA) drug.Cartilage, synovium, and meniscus samples from patients with OA were used to evaluate anabolic and antiinflammatory properties of R399E. In the rabbit joint instability model, 65 rabbits underwent transection of the anterior cruciate ligament plus partial meniscectomy. Three intraarticular (IA) R399E doses were administered biweekly 6 times, and static incapacitance was determined to assess joint pain. OA was evaluated 13 weeks after surgery. In sheep, medial meniscus transection was performed to induce OA, dynamic weight bearing was measured in-life, and OA was assessed after 13 weeks.Intermittent exposure to R399E (1 week per month) was sufficient to induce cell proliferation and release of anabolic markers in 3-dimensional chondrocyte cultures. R399E also inhibited the release of interleukin-1β (IL-1β), IL-6, and prostaglandin E2 from cartilage with synovium, meniscal cell, and synoviocyte cultures. In rabbits, the mean difference (95% confidence interval [95% CI]) in weight bearing for R399E compared to vehicle was -5.8 (95% confidence interval [95% CI] -9.54, -2.15), -7.2 (95% CI -10.93, -3.54), and -7.7 (95% CI -11.49, -3.84) for the 0.6, 6, and 60 μg doses, respectively, 6 hours after the first IA injection, and was statistically significant through the entire study for all doses. Cartilage surface structure improved with the 6-μg dose. Structural and symptomatic improvement with the same dose was confirmed in the sheep model of OA.R399E influences several pathologic processes contributing to OA, highlighting its potential as a disease-modifying therapy.
Genetic Influences in <scp>Cancer‐Associated</scp> Myositis
Authors: Karina Patasova, Ingrid E. Lundberg, Marie Holmqvist
Journal: Arthritis & Rheumatology (2022)

Idiopathic inflammatory myopathies (IIMs) comprise a heterogeneous group of rare immune‐mediated disorders that primarily affect muscles but also lead to dysfunction in other organs. Five different clinical subphenotypes of IIM have been distinguished: dermatomyositis, polymyositis, inclusion body myositis, antisynthetase syndrome, and immune‐mediated necrotizing myopathy. Excess mortality and morbidity associated with IIM are largely attributed to comorbidities, particularly cancer. The risk of malignancy is not equally distributed among IIM groups and is particularly high among patients with dermatomyositis. The cancer risk peaks around 3 years on either side of the IIM diagnosis and remains elevated even 10 years after the onset of the disease. Lung, colorectal, and ovarian neoplasms typically arise before the onset of IIM, whereas melanoma, cervical, oropharyngeal, and nonmelanoma skin cancers usually develop after IIM diagnosis. Given the close temporal proximity between IIM diagnosis and the emergence of malignancy, it has been proposed that IIM could be a consequence rather than a cause of cancer, a process known as a paramalignant phenomenon. Thus, a separate group of IIMs related to paramalignant phenomenon has been distinguished, known as cancer‐associated myositis (CAM). Although the relationship between IIM and cancer is widely recognized, the pathophysiology of CAM remains elusive. Given that genetic factors play a role in the development of IIM, dissection of the molecular mechanisms shared between IIM and cancer presents an opportunity to examine the role of autoimmunity in cancer development and progression. In this review, the evidence supporting the contribution of genetics to CAM will be discussed.
Chronic activation of pDCs in autoimmunity is linked to dysregulated ER stress and metabolic responses
Authors: Vidyanath Chaudhary, Marie Dominique Ah Kioon, Sung-Min Hwang, Bikash Mishra, Kimberly Lakin, Kyriakos A. Kirou, Jeffrey Zhang-Sun, R. Luke Wiseman, Robert F. Spiera, Mary K. Crow, Jessica K. Gordon, Juan R. Cubillos-Ruiz, Franck J. Barrat
Journal: The Journal of Experimental Medicine (2022)

Plasmacytoid dendritic cells (pDCs) chronically produce type I interferon (IFN-I) in autoimmune diseases, including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). We report that the IRE1α-XBP1 branch of the unfolded protein response (UPR) inhibits IFN-α production by TLR7- or TLR9-activated pDCs. In SSc patients, UPR gene expression was reduced in pDCs, which inversely correlated with IFN-I-stimulated gene expression. CXCL4, a chemokine highly secreted in SSc patients, downregulated IRE1α-XBP1-controlled genes and promoted IFN-α production by pDCs. Mechanistically, IRE1α-XBP1 activation rewired glycolysis to serine biosynthesis by inducing phosphoglycerate dehydrogenase (PHGDH) expression. This process reduced pyruvate access to the tricarboxylic acid (TCA) cycle and blunted mitochondrial ATP generation, which are essential for pDC IFN-I responses. Notably, PHGDH expression was reduced in pDCs from patients with SSc and SLE, and pharmacological blockade of TCA cycle reactions inhibited IFN-I responses in pDCs from these patients. Hence, modulating the IRE1α-XBP1-PHGDH axis may represent a hitherto unexplored strategy for alleviating chronic pDC activation in autoimmune disorders.
Re: Sophie Knipper, Mehrdad Mehdi Irai, Ricarda Simon, et al. Cohort Study of Oligorecurrent Prostate Cancer Patients: Oncological Outcomes of Patients Treated with Salvage Lymph Node Dissection via Prostate-specific Membrane Antigen-radioguided Surgery. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2022.05.031
Authors: Francesco Montorsi, Carlo Andrea Bravi, Giorgio Gandaglia, Alexandre Mottrie, Alberto Briganti
Journal: European Urology (2022)
Can extended reality in the metaverse revolutionise health communication?
Authors: Adéla Plechatá, Guido Makransky, Robert Böhm
Journal: npj Digital Medicine (2022)

In the metaverse, users will actively engage with 3D content using extended reality (XR). Such XR platforms can stimulate a revolution in health communication, moving from information-based to experience-based content. We outline three major application domains and describe how the XR affordances (presence, agency and embodiment) can improve healthy behaviour by targeting the users' threat and coping appraisal. We discuss how health communication via XR can help to address long-standing health challenges.
Abstract IA29: Present and future of precision oncology in hepatoblastoma
Authors: Carolina Armengol
Journal: Clinical Cancer Research (2022)

Abstract Pediatric liver cancer is rare (~1 case/1 million) with increasing incidence. The commonest tumor seen usually in young children and infants without underlying liver disease is hepatoblastoma (HB). Despite significant advances during last decades thanks to improvements in chemotherapeutic regimens and efficient surgical approaches, treatment options remain limited for ~20% of patients with aggressive resistant tumours and more than 40% survivors have long-term effects derived from treatment toxicity. Because of the rarity of the disease, global international efforts on clinical, pathological and biological fields are crucial to improve the current clinical management of HB. In this talk, current clinical patient stratification (Children's Hepatic tumors International Collaboration Hepatoblastoma Stratification, CHIC-HS) and treatment of patients with HB (Pediatric Hepatic International Tumor Trial, PHITT) will be exposed. The main clinical, pathological and biological prognostic factors used at present will be also explained. Since it is well-known that therapy response in oncology is intimately associated with cancer biology, the need to improve the current CHIC stratification by incorporating biological data will be emerged as a way to significant move forward towards precision medicine in pediatric liver cancer patients. Moreover, a summary of the latest advances in genomic, transcriptomic and methylation studies and the diagnostic/prognostic biomarkers as well as newest therapeutic targets/drugs will be exposed. As a rare disease, the unmet need for banking human samples, patient-derived cell lines and animal models to enable and boost translational research of childhood liver tumors will be stressed. Finally, Dr. Armengol will explain the latest advances on biological and pathological studies associated to PHITT in Europe, ranging from sample collection to identification and validation of diagnostic/prognostic biomarkers. The ongoing PHITT patient cohort and its associated biorepositories will be exposed as an exceptional opportunity to validate a panel of diagnostic and prognostic biomarkers and novel therapeutic strategies that could be incorporated in the upcoming clinical trial (PHITT-2). Nowadays, ongoing international efforts at clinical, pathological and biological level from the three main childhood liver study groups of Europe (SIOPEL), United States (COG) and Japan (JCCG) are being conducted and will move forward precision medicine in HB, impacting on the quality of life and survival of patients with HB in a near future. Citation Format: Carolina Armengol. Present and future of precision oncology in hepatoblastoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA29.
Abstract IA11: Molecular targeted therapies for advanced HCC
Authors: Josep M. Llovet
Journal: Clinical Cancer Research (2022)

Abstract Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. Current major advancements have impacted the management of patients with advanced HCC substantially improving their life expectancy. Several systemic therapies have resulted in positive III investigations (atezolizumab plus bevacizumab, durvalumab plus tremelimumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and two additional therapies obtained accelerated FDA approval owing to evidence of efficacy (pembrolizumab and nivolumab plus ipilimumab). Specifically, among TKIs, sorafenib and lenvatininb remain as first line option therapies in patients with contraindications or upon progression to immunotherapies. In second-line, regorafenib, cabozantinib and ramucirumab are the accepted choices. Few studies suggest that biomarkers or treatment related-AEs are associated with better outcome, as it is the case with hand-foot skin reaction with sorafenib, or AFP&amp;gt; 400 ng/ml or hypertension for ramucirumab. The fact that most HCC do not have a dominant actionable target has prevented precision oncology. Nonetheless, current studies are exploring abrogating main drivers previously unactionable, such as wnt signaling. The fact that TKI and VEGF-based MAb have also immunomodulatory activities has boosted their combination with immune therapies which nowadays are dominant in the landscape of management of HCC and ongoing phase III trials. Citation Format: Josep M. Llovet. Molecular targeted therapies for advanced HCC [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA11.